The adrenal cortex produces steroid hormones throughout postnatal life in response to stress and other physiological inputs. The endocrine cells of the cortex are constantly replenished, and the cortex remodels in response to prolonged changes in these inputs. While adrenocortical stem or progenitor populations that contribute to, and are regulated by, homeostatic and remodeling systems likely exist, the molecular identity of these cells, their location within the gland, and the intraadrenal signaling circuits that control their behavior are very poorly understood. The long-term goal is to understand the molecular and cellular logic that controls how the adrenal cortex is maintained and remodeled, an issue of interest from both basic and clinical scientific perspectives. The Sonic hedgehog (Shh) pathway was identified as a potential regulator of adrenal growth and remodeling, and a marker of adrenocortical progenitor and/or stem cell populations. Preliminary experiments led to the hypotheses that the Shh pathway plays critical roles in adrenocortical development, maintenance and remodeling, and identifies multiple adrenocortical progenitor and/or stem populations. These hypotheses will be tested in mouse models through three Aims. In the first Aim manipulations of Shh pathway activity in the adrenal cortex will test the hypotheses that Shh signaling plays multiple roles in the adrenal gland, including regulating capsule growth and maintenance, regulating steroidogenic cell differentiation and controlling a reciprocal signal produced by the capsule. In the second Aim murine genetic lineage tracing experiments will test the hypotheses that the adrenal cortical cells that make or receive the Shh signal have properties of progenitor or stem cells. The third Aim will address the functional relationship between Shh pathway activity and gland remodeling using two experimental paradigms - dietary salt manipulation and chronic adrenocorticotropin or dexamethasone administration- to test the hypothesis that dynamic hedgehog signaling influences cortical remodeling and that physiological inputs regulate Shh pathway activity and modulate the fate of the progenitors identified by Shh signaling. Together these experiments will advance our understanding of adrenal biology by exploring novel molecular mechanisms that influence maintenance and remodeling of this important gland. They also will more broadly contribute to our understanding of the interface between signaling systems and animal physiology. PUBLIC HEALTH RELEVANCE: The cortex, or outer region, of the adrenal gland produces steroid hormones throughout life; if hormone production is disrupted due to genetic mutation, as occurs in about 1:15000 people, it is lethal without lifelong daily hormone replacement therapy. This project will study the molecular mechanisms that maintain the cells in the adrenal cortex that produce steroids. Greater understanding of these mechanisms may lead to improved management of adrenal disorders and ultimately perhaps ways to treat patients by gene repair and cell replacement therapy.